Investigations into derivatives of aspartic acid as non-nutritive sweeteners stem from the accidental discovery that L-aspartyl-L-phenylalanine methyl ester (Aspartame.RTM.) is sweet, 100-150 times sucrose, and free of unpleasant aftertaste. R. H. Mazur, J. M. Schlatter, and A. H. Goldkamp, JACS, 91, 2684 (1969). The authors disclosed that the L-aspartic acid portion of the molecule is critical for sweetness, but that considerable modification of the phenylalanine portion could be tolerated.
Subsequent work investigated the structural relationships of aspartic acid amides as regards sweetness. R. H. Mazur, A. H. Goldkamp, P. A. James, and J. M. Schlatter, J. Med. Chem. 13, 12-17 (1970). The authors' investigations revealed that the structural requirements for good sweetness in derivatives of L-aspartic acid are quite specific, as is revealed by tests of the L-aspartate amides: ##STR1## 4-methylpentylamide--tasteless 1-ethylbutylamide--bitter
hexylamide--sweet, 1-2 X sucrose PA1 heptylamide--sweet, 1-2 X sucrose PA1 1-methylbutylamide--tasteless PA1 1-methylpentylamide--sweet, 30 X sucrose PA1 1-methylhexylamide--sweet, 20-50 X sucrose PA1 1-methylheptylamide--sweet, 10 X sucrose PA1 1,3-dimethylbutylamide--bitter PA1 1,3-dimethylpentylamide--sweet, 1-2 X sucrose PA1 1,4-dimethylpentylamide--sweet, 50-100 X sucrose PA1 1-hydroxymethyl-4,4-dimethylpentylamide PA1 1-hydroxymethyl-5-methylhexylamide PA1 1-hydroxymethylhexylamide PA1 1-hydroxymethyl-4-methylhexylamide PA1 1-hydroxymethyl-4,4-dimethylhexylamide PA1 1-hydroxymethylpentylamide PA1 1-hydroxymethyl-5,5-dimethylhexylamide
All the sweet isomers were found to be L--L. The 1-methylhexylamide was about 20-50 times the sweetness of sucrose and the 1,4-dimethylpentylamide was about 50-100 times the sweetness of sucrose.
British Pat. No. 1,381,826, Neely, January 29, 1975, claims the use of L-aspartyl-L-1,4-dimethylpentylamide in oral compositions as a sweetener.
Y. Ariyoshi, N. Yasuda, K. Yamatani, Bull. Chem. Soc. Japan, 47, 326 (1974) describe investigations into the sweetness of hydroxy-substituted derivatives of L-aspartyl dipeptides. They report that .alpha.-L-aspartyl-L-1-methyl-2-phenethylamine (aspartyl amphetamine) was 50 times as sweet as sucrose; however, L-aspartyl-L-1-hydroxymethyl-2-methyl-2-phenethylamine was only 1 to 2 times as sweet as sugar. The authors report that with an L,L configuration, hydroxyl substitution always decreased potency of sweetness, while with L,D configurations, hydroxy substitution sometimes increased potency and sometimes decreased it. Methyl substitution at the 2 or 3 position produced bitter tasting compounds.
1-(1-hydroxyethyl) derivatives of .alpha.-L-aspartic acid have no sweetness. L. B. P. Brusse, H. C. Peer, A. van der Heijden, Z. Lebensm. Unters. Forsch., 159, 339 (1975).
M. Miyoshi, K. Nunami, H. Sugano, T. Fujii, Bull. Chem. Soc. Japan, 51, 1433 (1978) disclose L-aspartyl dipeptides of the formula: ##STR2## as being sweet. The authors state that none of the O-acyl-L-aspartylamino-L-alkanols synthesized were sweet and that the C-terminal amino acid must be the D form to exhibit sweetness.
Belgian Pat. No. 851,368, Ferrer, May 5, 1977 discloses the compound .alpha.-L-aspartyl-1,5-dimethyl-5-hydroxyhexylamide (claimed as the L-aspartate of 6-amino-2-methyl-2-heptanol) for use in the treatment of cardiac and pulmonary insufficiency.
In the gastrointestinal tract, L-aspartyl alkaneamides and L-aspartyl-1-hydroxymethyl alkaneamides are hydrolyzed to aspartic acid and the corresponding amine by aminopeptidase enzymes. E. F. Marsh, D. A. Herring, J. Pharm. Exp. Therapy, 102-178 (1951) describe a study of the comparative pharmacology of hydroxyl and methyl derivatives of 1,5-dimethylhexylamine (named as 6-methyl-2-heptylamine by the authors). These compounds would be produced by the hydrolysis of the L-aspartyl dimethylhexylamide. The data show the amine compound to have vasopressor and myocardial stimulant activity. This activity is shown to be lessened somewhat by 5-hydroxyl or 2- or 3-methyl substitution. 1,5-dimethylhexylamine has been sold commercially as a vasoconstrictor (Octodrine); 1,3-dimethyl pentylamine has been sold as a vasoconstrictor (Forthane); 1,5-dimethylaminohexan-5-ol hydrochloride has been sold as a cardiac stimulant and coronary vasodilator (Heptanol).